The objective of this grant application is to develop a rational approach to therapy of sudden cardiac death through understanding of the pathogenesis of ventricular fibrillation (VF) and electrical defibrillation at the mechanistic level. We have demonstrated that dynamic factors, such as electrical restitution and excitability, contribute to initiation and maintenance of wavebreak during VF. Alteration of these dynamic factors results in two types of VF in rabbit ventricles. The type 1 VF is associated with steep action potential duration (APD) restitution, normal excitability and multiple wavelets. Type 2 VF is associated with flat APD restitution, reduced excitability and spatiotemporal periodicity. We also developed methods to simultaneous map membrane potential (Vm) and intracellular calcium (Cai) in normal and diseased rabbit ventricles. Preliminary results suggest that Cai cycling is a critical factor that controls multiple aspects of dynamic wave stability. Furthermore, we found that Cai cycling might also play a role in the mechanisms of electrical defibrillation. Because electrical shock is the only effective therapy for VF, we propose to perform further investigations on the importance of Cai cycling in the mechanisms of ventricular defibrillation. We will use normal rabbits and rabbit models of ischemic cardiomyopathy and pacing-induced cardiomyopathy to pursue these studies. Simultaneous Vm and Cai mapping and single cell transmembrane potential recordings will be used to determine the relationship between Cai cycling, afterdepolarizations and triggered activity after defibrillation shocks. The Specific Aim 1 will test the hypothesis that Cai cycling is important in the post-shock re-initiation of Type 1 VF. The Specific Aim 2 will test the hypothesis that Cai cycling is important in the post-shock reinitiation of Type 2 VF. The Specific Aim 3 will test the hypothesis that Cai cycling is important in determining the upper limit of vulnerability. We expect that these studies will improve the understanding of the mechanisms of ventricular defibrillation and lead to better management of patients at risk of sudden cardiac death.